CORRELATION BETWEEN CHEMICAL-STRUCTURE, RECEPTOR-BINDING, AND BIOLOGICAL-ACTIVITY OF SOME NOVEL, HIGHLY-ACTIVE, 16-ALPHA-ACETAL-SUBSTITUTED, 17-ALPHA-ACETAL-SUBSTITUTED GLUCOCORTICOIDS

  • 1 January 1984
    • journal article
    • research article
    • Vol. 25  (1) , 70-78
Abstract
The affinity for the glucocorticoid receptor in rat skeletal muscle of some glucocorticoids with a net type of 16.alpha.,17.alpha.-acetal substituent was estimated and correlated to the glucocorticoid activities in 3 in vivo systems in rats. Budesonide (an approximately 1:1 mixture of the C(22) epimers of 11.beta.,21-dihydroxy-16.alpha.,17.alpha.-[(22R,S)-propylmethylenedioxy]-pregna-1,4-diene-3,20-dione) and the isolated (22R)- and (22S)-epimers bound to the same binding site as the potent glucocorticoids dexamethasone (DEX) or triamcinolone 16.alpha.,17.alpha.-acetonide (TA), but with even higher affinity than DEX or TA, despite the lack of a 9.alpha.-fluro atom in budesonide and its epimers. The (22R)-epimer was twice as active as the (22S)-epimer, 4 times more active than TA and 14 times more active than DEX. The introduction of a 9.alpha.-fluoro atom slightly decreased the binding affinity of the (22R)-epimer of budesonide, in contrast to the positive effect of 9.alpha.-fluorination of, e.g., 16.alpha.,17.alpha.-acetonides. The negative influence of 9.alpha.-fluorination of the (22R)-epimer was partially reversed in the 6.alpha.,9.alpha.-difluorinated (22R)-epimer. The fluorinated compounds were more active than DEX and TA (8 and 11 times more active than DEX, and 2 and 3 times more active than TA, in the case of 9.alpha.-fluoro- and 6.alpha.,9.alpha.-difluoro-derivatives of the (22R)-epimer, respectively). Budesonide is metabolized mainly to 16.alpha.-hydroxyprednisolone (11.beta.,16.alpha.,17.alpha.,21-tetrahydroxy-pregna-1,4-diene-3,20-dione) and 6.beta.-hydroxy-budesonide. Both metabolites were very weak competitors for the ligand-binding sites on the receptor (3 and 6% of the affinity of DEX, respectively). The affinity for the receptor in vitro was closely correlated to the topical glucocorticoid activity in vivo for the 12 steroids compared (r = 0.98; R = 0.98), which supports the contention that in vitro tests for receptor affinity are useful when screening for agonists among steroids with the present type of structures. The results on receptor-ligand interaction are in accordance with X-ray crystallographic data available for some steroids.

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